Describing the Weight-Reduced State: Physiology, Behavior, and Interventions

Abstract

Although many persons with obesity can lose weight by lifestyle (diet and physical activity) therapy, successful long-term weight loss is difficult to achieve, and most people who lose weight regain their lost weight over time. The neurohormonal, physiological, and behavioral factors that promote weight recidivism are unclear and complex. The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop in June 2019, titled "The Physiology of the Weight-Reduced State," to explore the mechanisms and integrative physiology of adaptations in appetite, energy expenditure, and thermogenesis that occur in the weight-reduced state and that may oppose weight-loss maintenance. The proceedings from the first session of this workshop are presented here. Drs. Michael Rosenbaum, Kevin Hall, and Rudolph Leibel discussed the physiological factors that contribute to weight regain; Dr. Michael Lowe discussed the biobehavioral issues involved in weight-loss maintenance; Dr. John Jakicic discussed the influence of physical activity on long-term weight-loss maintenance; and Dr. Louis Aronne discussed the ability of drug therapy to maintain weight loss.

Figure 1

Changes from baseline in energy balance and homeostatic systems during maintenance of a 10% or greater reduced body weight and responsiveness to exogenous leptin in individuals who initially had obesity or never had obesity (9). Energy expenditure owing to physical activity is calculated as the difference between direct measurement of 24-hour energy expenditure and measurement of resting energy expenditure plus diet-induced thermogenesis. Eating behavior, including energy intake, is examined by visual analog scales during a fixed liquid formula meal, kilocalories of the liquid formula consumed to reach satiation, and functional MRI (fMRI) studies of brain responses to food. Assessments of autonomic nervous system activity were made by analyses of heart rate variability during sequential blockade of the PNS and SNS with atropine and esmolol, respectively, and by 24-hour urine catecholamine excretion. Skeletal muscle contractile efficiency was measured by graded bicycle ergometry. MHC and SERCA muscle gene expression studies were done by mRNA quantification in biopsies of vastus lateralis muscle. Entries in bold are at least partially reversed by leptin repletion in weight-reduced individuals. MCH, myosin heavy chain; PNS, parasympathetic nervous system; rT3, reverse T3; SERCA, sarcoplasmic endoplasmic reticulum Ca⁺⁺-dependent ATPase; SNS, sympathetic nervous system; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone.

Figure 2

Mathematical model simulations of the mean changes in body composition and energy balance dynamics of 35 men with overweight (mean BMI = 26 kg/m²) with mean age of 40.5 years participating in a 2-year intervention designed to reduce energy intake by 25% (22). (A) Body weight (•) and body fat (Δ) data along with model simulations (curves) showing the rapid early losses followed by a plateau at 12 months. (B) Mean data for changes in energy expenditure (○) and intake (□), along with error bars representing standard errors, were plotted along with the mean model simulations (curves) showing rapid early decreases in both energy expenditure and intake followed by a progressive exponential rise in intake to eventually balance expenditure at 12 months. (C) Model-predicted increases in appetite (dashed curve) were calculated assuming that, for each kilogram of lost weight, appetite increased above baseline by 95 kcal/d. Following the initial reduction in energy intake, its subsequent exponential increase toward baseline (solid blue curve) was an expected response of a persistent and approximately constant effort to adhere to the prescribed diet intervention as quantified by the difference between the dashed appetite and solid intake curves.

Figure 3

A threshold model for leptin action. There are similar responses to declines in leptin beyond individualized “thresholds.” These thresholds are lower in individuals who have never had obesity than in those with obesity. A weight-reduced individual with obesity may thus invoke the potent metabolic and behavioral opposition to sustained weight loss at levels of energy stores and leptin that would not invoke these changes in an individual who has never had obesity.

Figure 4

Three years’ treatment with liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes. Both arms had dietary intervention.

Figure 5

Combination therapy can produce greater weight loss: doubling the dose of either phentermine or topiramate does not double the weight loss, whereas adding phentermine to topiramate does give additive weight loss.

Figure 6

Categorical analysis of >5% or >10% weight loss and maintenance in patients treated with anti-obesity medications at an academic center.